Objective-LOX-1, a novel lectin-like receptor for oxidized LDL (ox-LDL), is expressed in response to ox-LDL, angiotensin II (Ang II), tumor necrosis factor (TNF)-␣, and other stress stimuli. It is highly expressed in atherosclerotic tissues. Peroxisome proliferator-activated receptor (PPAR)-␥ ligands, such as pioglitazone, exert antiatherosclerotic effects. This study examined the regulation of LOX-1 expression in human coronary artery endothelial cells (HCAECs) by pioglitazone. Methods and

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... lts-Fourth generation HCAECs were treated with ox-LDL, Ang II, or TNF-␣ with or without pioglitazone pretreatment. All 3 stimuli upregulated LOX-1 expression (mRNA and protein). Pioglitazone, in a concentration-dependent manner, reduced LOX-1 expression (PϽ0.01 versus ox-LDL, Ang II, or TNF-␣ alone). Ox-LDL, Ang II, and TNF-␣ each enhanced intracellular superoxide radical generation, and pioglitazone pretreatment reduced superoxide generation (PϽ0.01 versus ox-LDL, Ang II, or TNF-␣). Furthermore, all 3 stimuli upregulated the expression of the transcription factors nuclear factor-B and activator protein-1 (determined by electrophoretic mobility shift assay), and pioglitazone pretreatment reduced this expression (PϽ0.01 versus ox-LDL, Ang II, or TNF-␣). To determine the biological significance of pioglitazone-mediated downregulation of LOX-1, we studied monocyte adhesion to ox-LDL-treated HCAECs. Pioglitazone reduced the adhesion of monocytes to activated HCAECs in a fashion similar to that produced by antisense to LOX-1 mRNA. Conclusions-These observations suggest that the PPAR-␥ ligand pioglitazone reduces intracellular superoxide radical generation and subsequently reduces the expression of transcription factors, expression of the LOX-1 gene, and monocyte adhesion to activated endothelium. The salutary effect of PPAR-␥ ligands in atherogenesis may involve the inhibition of LOX-1 and the adhesion of monocytes to endothelium. (Arterioscler Thromb Vasc Biol. 2003;23:2203-2208.) Key Words: angiotensin Ⅲ atherosclerosis Ⅲ oxidized LDL Ⅲ peroxisome proliferator-activated receptor-␥ Ⅲ tumor necrosis factor-␣ E ndothelial dysfunction elicited by oxidized LDL (ox-